tbuckley/cabot-search huggingface dataset:
Abstract 342: Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive cancers
Authors: Martina S. McDermott, Ke Wei Gong, Neil A. O'Brien, Dylan Conklin, Benjamin Hoffstrom, Ming Lu, Jun Zhang, Tong Luo, Weiping Jia, Jenny J. Hong, Kevin Chau, Simon Davenport, Michael F. Press, Abram Handly-Santana, Joan S. Brugge, Ronny Drapkin, John A. Glaspy, Leonard Presta, Dennis J. Slamon
Journal: Cancer Research (2022)

Abstract Background: Claudin 6 (CLDN6), a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies including ovarian and endometrial cancers. Conversely it has little or no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of potential therapeutic antibody-drug conjugates (ADCs). This study describes the generation and preclinical characterization of an anti-CLDN6 ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to MMAE via a cleavable linker. Materials and Methods: A fully humanized anti-CLDN6 antibody was initially characterized for binding affinity, selectivity/specificity, internalization characteristics and in vivo efficacy. It was then conjugated to MMAE resulting in the potential therapeutic anti-CLDN6 ADC. The anti-tumor efficacy of the ADC was next assessed for anti-tumor efficacy in CLDN6 positive (CLDN6+) and negative (CLDN6-) xenografts and patient-derived xenograft (PDX) models of specific cancers including ovarian and endometrial cancer. Results: Selective binding of the ADC to CLDN6, without cross reactivity to other CLDN family members CLDN3, CLDN4 and CLDN9, was confirmed in human cancer cell lines and cells engineered to overexpress each protein. The ADC was also shown to rapidly internalize in CLDN6+ cells. Robust tumor regressions following treatment with the ADC were observed in CLDN6+ xenografts that were sustained beyond the treatment window. Conversely, there was limited to no activity of the ADC in CLDN6- xenografts models. In addition, the prevalence of CLDN6 expression in human ovarian and endometrial cancers was assessed by IHC in tissue microarrays and found to be 28% (ovarian epithelial carcinomas) and 11% (endometrial carcinomas), respectively. Discussion: Overall, these data suggest that our anti-CLDN6 ADC may be a promising treatment for patients with CLDN6+ tumors and it is currently in Phase I clinical testing. Citation Format: Martina S. McDermott, Ke Wei Gong, Neil A. O'Brien, Dylan Conklin, Benjamin Hoffstrom, Ming Lu, Jun Zhang, Tong Luo, Weiping Jia, Jenny J. Hong, Kevin Chau, Simon Davenport, Michael F. Press, Abram Handly-Santana, Joan S. Brugge, Ronny Drapkin, John A. Glaspy, Leonard Presta, Dennis J. Slamon. Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 342.
Abstract 1464: Zaniya Mark
Authors: Zaniya A. Mark, Guoliang Li, Robert Matusik, Zhenbang Chen
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is one of the most common types of cancers diagnosed in American men. Moreover, PCa malignancy disproportionally strikes more on African American (AA) men than any other ethnic groups including Caucasian American (CA) men. Forkhead Box A1 (FOXA1) is frequently mutated in hormone receptor-driven cancers including PCa. FOXA1 mutation rates in AA PCa specimens are 3-fold higher than that in CA PCa. By annotating the FOXA1 mutation landscape two hotspots were defined in AA PCa patients located in the forkhead domain: D226N and R219C. FOXA1 expression and functions are regulated by lysine [K]-specific demethylase 5B (KDM5B). KDM5B contributes to the activation of signaling pathways that promote cancer progression. Here in this project, we will focus on the mechanistic role of FOXA1 dysregulation and its interaction with KDM5B and AR on PCa progression in AA vs CA PCa cells. Therefore, we hypothesize that the dysregulation of FOXA1 plays an essential role in the progression of PCa by altering chromatin remodeling and AR interaction, and FOXA1 mutation promotes more aggressive malignancies in AA PCa cells. In order to investigate the biological function and regulation of FOXA1 in PCa cells we first need to knockout (KO) the endogenous expression using CRISPR technology and then knockin (KI) the unique mutants R219C and D226N. These in vitro studies of FOXA1 mutations found in AA PCa will be critical to determine the biological functions of these mutants for PCa progression. The findings from this study will provide valuable insights into the contributions of the FOXA1 regulation and will add to our knowledge base for the potential development of a novel therapeutic strategy to reduce PCa disparities between AA and CA populations. This project was supported, in part, by MVTCP Cancer Partnership Grant U54 CA163069. Citation Format: Zaniya A. Mark, Guoliang Li, Robert Matusik, Zhenbang Chen. Zaniya Mark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1464.
Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets
Authors: Xiaoping Sun, Thomas Nguyen, Achouak Achour, Annette Ko, Jeffrey Cifello, Chen Ling, Jay Sharma, Toyoko Hiroi, Yongqing Zhang, Chee W. Chia, William Wood, Wells W. Wu, Linda Zukley, Je-Nie Phue, Kevin G. Becker, Rong-Fong Shen, Luigi Ferrucci, Nan-ping Weng
Journal: Journal of Clinical Investigation (2022)

A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier–based (UMI-based) RNA-seq method. Thorough analysis of 1.9 × 108 T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 × 108. Alterations of the TCR repertoire with age were observed in all 4 subsets of T cells. The greatest reduction was observed in naive CD8+ T cells, while the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting that aging has a more profound effect on cytotoxic as opposed to helper T cell functions. This may explain the increased susceptibility of older adults to novel infections.
Abstract 5090: Prognosis of renal cell carcinoma patients with VHL mutations to immune checkpoint inhibitors
Authors: Dong Shen, Yufeng Huang, Zhiwei Wu, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai
Journal: Cancer Research (2022)

Abstract Background: The von Hippel-Lindau (VHL) gene is a tumor suppressor gene. Although VHL gene alterations play a key role in the pathogenesis of renal cell carcinoma (RCC), and several therapies targeting this molecular pathway have been studied, such as sunitinib, pazopanib and axitinib. However, it is not clear whether VHL mutation is a prognostic factor for immunotherapy in renal cell carcinoma. Methods: The impact of VHL mutations on survival outcomes in RCC patients received immunotherapy or non-immunotherapy were verified in the Memorial Sloan Kettering Cancer Center (MSKCC) trials and The Cancer Genome Atlas (TCGA) RCC cohort, respectively. An in-house Chinese RCC cohort (n=950) was used for the analysis of immune-related markers. The relationship between clinical pathologic features and VHL were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: In the MSKCC cohort, a total of 143 RCC patients receiving immunotherapy were enrolled, of which 117 (81.8%) were clear cell RCC and 143 (100%) microsatellite-stable RCC. VHL mutation was significantly associated with high TMB score (P =0.017). Kaplan-Meier survival analysis showed that patients with VHL mutation obtained better OS compared to VHL wild-type (50 months vs. 23 months, HR, 0.36; 95% CI 0.21-0.64; P&amp;lt;0.001). In the TCGA cohort, all RCC patients received non- immunotherapy. No association was observed between VHL and OS (HR, 1.00; 95% CI 0.73-1.38; P=0.981). VHL mutations were significantly associated with higher TMB levels (P=0.006) and MSI-H (P=0.004) in the in-house Chinese RCC cohorts. Conclusions: Our results suggest that VHL mutation may be associated with better OS in RCC patients receiving immunotherapy. The exact mechanisms underlying VHL are needed to be further evaluated. Citation Format: Dong Shen, Yufeng Huang, Zhiwei Wu, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. Prognosis of renal cell carcinoma patients with VHL mutations to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5090.
Association of Sitting Time With Mortality and Cardiovascular Events in High-Income, Middle-Income, and Low-Income Countries
Authors: Sidong Li, Scott A. Lear, Sumathy Rangarajan, Bo Hu, Lu Yin, Shrikant I. Bangdiwala, Khalid F. Alhabib, Annika Rosengren, Rajeev Gupta, Prem K. Mony, Andreas Wielgosz, Omar Rahman, M. Y. Mazapuspavina, Alvaro Avezum, Aytekin Oguz, Karen Yeates, Fernando Lanas, Antonio Dans, Marc Evans M. Abat, Afzalhussein Yusufali, Rafael Diaz, Patricio Lopez-Jaramillo, Lloyd Leach, P. V. M. Lakshmi, Alicja Basiak-Rasała, Romaina Iqbal, Roya Kelishadi, Jephat Chifamba, Rasha Khatib, Wei Li, Salim Yusuf
Journal: JAMA Cardiology (2022)

High amounts of sitting time are associated with increased risks of cardiovascular disease (CVD) and mortality in high-income countries, but it is unknown whether risks also increase in low- and middle-income countries.
Abstract 366: Combinatorial effect of fisetin and paclitaxel encapsulated PBM nanoparticles in ovarian cancer therapy
Authors: Melayshia McFadden, Santosh Kumar Singh, Rajesh Singh
Journal: Cancer Research (2022)

Abstract High-grade Serous Ovarian Cancer (HGSOC) accounts for 68% of Ovarian Cancers (OvCas). It is a clinically aggressive neoplasm that even after treatment, a substantial proportion of advanced OvCas will develop resistance within 18 months. Thus, it is imperative to formulate anti-cancer agents that target cancer cells without affecting normal cells. The proposed study evaluated a novel method for targeted delivery of fisetin alone or combined with paclitaxel (PTX) at desired rates. We have used a natural polysaccharide (starch; FDA approved) as a core for planetary ball milled (PBM) nanoparticles which binds high-affinity folate receptors on OvCa cells via folate conjugated poly (ε-caprolactone)/poly (ethylene glycol) copolymer coating of the PBM nanoparticles. Treatment of OvCa cells (CAOV-3 and OVCAR-3) with PBM-NPs has shown its cytotoxic effect. The cell viability (MTT) assay was performed to determine the optimal IC50 values of fisetin, PTX alone, and in combination. These particles are rapidly internalized and induce significant cancer cell death at lower doses than unformulated fisetin or PTX. Importantly, negative controls showed that PBM nanoparticles without fisetin or paclitaxel have no toxic effects on OvCa cells. The immunofluorescence study confirmed the effectiveness of the combined drug; dead nuclei were found more within the cells treated by the combination than fisetin or PTX alone. The combined drug treatment was most effective in inhibiting proliferation and inducing apoptosis; accordingly, it showed noticeable increases in pro-apoptotic (BAX, BID), apoptotic (PARP, Caspase-3), and decreases in anti-apoptotic genes (BCL-XL and MCL-1) gene in a western blot and RT-PCR analysis. Taken together, we observed that the combination of PTX and fisetin resulted in significant cytotoxicity and apoptosis as compared to alone. Our results suggest that fisetin can be a potential agent in enhancing the efficacy of PTX in OvCa treatment. These finding highlights the promising role of natural bioactive compounds and provide the rationale for further transitional research. Citation Format: Melayshia McFadden, Santosh Kumar Singh, Rajesh Singh. Combinatorial effect of fisetin and paclitaxel encapsulated PBM nanoparticles in ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 366.
Abstract 5451: New organoselenium compounds with cytotoxic activity <i>in vitro</i> and <i>in vivo</i> towards colon cancer
Authors: Sandra Ramos-Inza, Cesar Aliaga, Asif Raza, Ignacio Encío, Arun Sharma, Carmen Sanmartín, Daniel Plano
Journal: Cancer Research (2022)

Abstract Colon cancer is currently the third most common diagnosed cancer and the second leading cause of cancer death worldwide. The inclusion of a selenium atom (Se) in organic molecules has been shown to be a valid approximation in the design of novel chemotherapeutic agents with antitumoral activity. On the other hand, non-steroidal anti-inflammatory drugs (NSAIDs) have gained interest in recent years in terms of their chemopreventive and chemotherapeutic use for cancer treatment whether they are evaluated alone, as a combination therapy, or in the form of structurally modified analogs. Considering these findings, we have designed five novel NSAID derivatives containing Se in their structure. The cytotoxicity and selectivity of the new compounds were evaluated in a panel of 10 cancer cell lines including breast, prostate, lung, and colon cancer, and in two non-malignant cell lines. Compound 5 was the most cytotoxic derivative with IC50 values below 10 µM in all the cancer cell lines tested, and it was also the most selectively toxic towards cancer cells while sparing the non-malignant cell lines. The efficacy of compound 5 in vivo was assessed in a subcutaneous colon cancer xenograft mouse model and it showed a significant inhibition of the tumor growth. Taken together, this work supports that the novel Se-NSAID combination provides a feasible frame to develop new agents with potent antitumoral properties Citation Format: Sandra Ramos-Inza, Cesar Aliaga, Asif Raza, Ignacio Encío, Arun Sharma, Carmen Sanmartín, Daniel Plano. New organoselenium compounds with cytotoxic activity in vitro and in vivo towards colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5451.
Abstract 6391: Scalable colorectal cancer (CRC) diagnosis model with arterial and unenhanced phases of KRAS mutational status using Apache Spark
Authors: Mary Adetutu Adewunmi
Journal: Cancer Research (2022)

Abstract The exponential increase in Medical data and Computer-aided diagnostic tools has made it easier for Machine Learning (ML) Researchers to extract valuable insights from medical images resulting in better patient outcomes during Medical Summarization. According to current statistics, 8.8 million people died every year due to cancer death. It is therefore imperative to use these available image datasets for better diagnosis, increased patient outcomes and recovery from deadly diseases. As a result, this study proposes a Colorectal Cancer classification model for detecting KRAS mutation status of Patients through their Radiomic images using the transfer learning of a deep learning pipeline on Apache Spark. The datasets will be curated from National Cancer Institute (NCI), features extraction or classification of Computed tomography(CT) images into CT- based handcrafted radiomic signatures with a Convolutional Neural Network(CNN) using the Apache Spark framework, the system uploads the segmented scanning images to the High Distributed File System (HDFS), Confidence Interval(CI), Area Under Curve(AUC), Precision and Recall for Validation cohort, Docker for app deployment and containerization of the model developed for reproducibility, transfer learning and model reuse. The result would be a real-time model using Deep learning pipelines with Apache Spark and Keras Tensor flow for KRAS Mutation detection using Colorectal Cancer images. In conclusion, this research project would produce a scalable and reproducible model for the faster diagnosis of Colorectal Cancer through the KRAS mutation status of CRC Patients. Citation Format: Mary Adetutu Adewunmi. Scalable colorectal cancer (CRC) diagnosis model with arterial and unenhanced phases of KRAS mutational status using Apache Spark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6391.
Abstract 724: Examining the effects of obesity and weight loss on mammary tumor inflammation and fibrosis
Authors: Genevra M. Kuziel, Lisa M. Arendt
Journal: Cancer Research (2022)

Abstract Obesity significantly increases risk of breast cancer development, and following diagnosis, obese breast cancer patients have an overall worsened prognosis. The complex relationship of obesity to breast cancer growth and aggressiveness must continue to be examined. Within breast adipose tissue, obesity causes a state of chronic, macrophage-driven inflammation. Chronic inflammation is associated with increased extracellular matrix (ECM) deposition. Increased collagen within the mammary microenvironment is a risk factor for tumor formation, as well as more aggressive tumors, in mouse models. In breast tumors from obese patients, tumor desmoplasia is also found to be increased. To better understand how obesity affects mammary tumor growth, inflammation, and fibrosis, we used a diet-induced obesity mouse model paired with the estrogen receptor alpha (ERα)+ TC2 mammary tumor cell line in female FVB mice. We observed that TC2 mammary tumors grew significantly faster in obese mice compared to lean mice and had significantly more macrophage infiltration. TC2 tumors from obese mice also had significantly more collagen deposition than TC2 tumors from lean mice, indicating that obesity leads to more fibrotic tumors. To identify how weight loss alters the mammary gland and mammary tumor microenvironments, obese mice were switched from a high-fat diet to a low-fat diet for six weeks, to induce weight loss. In non-tumor-bearing mammary glands, weight loss led to a significantly decreased number of crown-like structures, a marker of adipose tissue inflammation, similar to observations in human adipose tissue. TC2 mammary tumors grew at an intermediate rate between tumors from lean and obese mice, indicating that weight loss may be a viable option to reduce tumor aggressiveness, particularly for obese patients with other breast cancer risk factors. Understanding these weight-related changes in the mammary gland and mammary tumor microenvironments will provide greater insight into possible interventions for obese breast cancer patients. Citation Format: Genevra M. Kuziel, Lisa M. Arendt. Examining the effects of obesity and weight loss on mammary tumor inflammation and fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 724.
Abstract 5605: BH3120: A novel bispecific antibody targeting 4-1BB and PD-L1 with well balanced efficacy and safety profiles
Authors: Jiangcheng Xu, Yang Liu, Jing Wang, Fei Fan, Haitao Gu, Lanxin Zhang, Jun Wang, Ding Song, Ailong Guo, Hongjuan Zhang, Kaixuan Su, Jiaojiao Su, Lijuan Li, Jingmei Cai, Aihong Zhang, Jiawang Liu, Kyoungwoo Lee
Journal: Cancer Research (2022)

Abstract 4-1BB (CD137, TNFSF9) is a promising co-stimulatory signaling mediator of T cells and NK cells, and agonistic monoclonal antibodies targeting 4-1BB are under clinical investigations aiming to observe sufficient and prolonged anti-tumor efficacy. However, these trials have resulted in limited efficacy or safety, and different bispecific approaches are being explored to improve the profiles. BH3120, a bivalent bispecific antibody generated by Pentambody(TM) platform targeting 4-1BB and PD-L1 simultaneously, demonstrates strong and prolonged antitumor efficacy as monotherapy in in vivo studies, and favorable safety profiles up to 200mg/kg/dose in non-human primates. Moreover, combination of BH3120 with an immune checkpoint inhibitor shows synergistically enhanced anti-tumor efficacy. Supported by these results, IND enabling studies of BH3120 are on-going and clinical evaluations are planned from later in 2022. Citation Format: Jiangcheng Xu, Yang Liu, Jing Wang, Fei Fan, Haitao Gu, Lanxin Zhang, Jun Wang, Ding Song, Ailong Guo, Hongjuan Zhang, Kaixuan Su, Jiaojiao Su, Lijuan Li, Jingmei Cai, Aihong Zhang, Jiawang Liu, Kyoungwoo Lee. BH3120: A novel bispecific antibody targeting 4-1BB and PD-L1 with well balanced efficacy and safety profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5605.